Creation of transgenic mice by introduction of new or mutated genes into the germ line of a mouse has been proven to be useful for understanding function of proteins and developmental regulation of genes. The purpose of this project is to create transgenic mice as animal models for studying the molecular basis of genetic and acquired connective tissue diseases. These transgenic mice will also be used to elucidate the mechanisms by which the genes for extracellular matrix proteins and their receptors are regulated in a developmental-specific manner. Creation of transgenic animals which carry mutated exogenous genes for basement membrane and cartilage components have been exploited. Constructs containing a reporter gene under the direction of the promoter and the enhancer of these genes have been injected into mouse oocytes to identify sequences necessary for tissue specific regulation of these genes. These regulatory sequences are being used to express a foreign gene in specific tissues of transgenic mice, and these transgenic animals may be used as models for human diseases such as arthritis and diabetes. The creation of specific alterations in basement membrane and cartilage genes at their native chromosomal loci in mice by homologous recombination has also been attempted. By using gene targeting in embryonic stem cells, mutations of specific sites within genes can be introduced in the mouse germ line to assess the role of these genes in the whole animal.